Body Roundness Index Is Better Correlated with Insulin Sensitivity than Body Shape Index in Young and Middle-Aged Japanese Persons

Aims: The present study aimed to clarify the relationships between novel and traditional anthropometric indices and insulin sensitivity (SI) in young and middle-aged Japanese persons with normal glucose tolerance (NGT), and middle-aged Japanese persons with NGT and glucose intolerance. Methods: Plasma glucose and insulin levels were measured in 1270 young (age <40 years) and 2153 middle-aged persons with NGT (n = 1531) and glucose intolerance (n = 622) during a 75-g oral glucose tolerance test. Height (Ht), weight, and waist circumference (WC) were measured. The body mass index (BMI), WC, and the WC/Ht ratio were used as traditional anthropometric indices. A body shape index (ABSI) and the body roundness index (BRI) were calculated as novel indices. Indices of SI (Matsuda index and 1/homeostasis model assessment of insulin resistance) were calculated and compared with anthropometric indices. Results: The ABSI showed a weak correlation with SI indices in all groups. The BRI showed almost the same correlation with SI indices as the BMI, WC, and WC/Ht in all groups. The inverse correlation between each of the anthropometric indices other than ABSI and SI indices was weak in young persons, at 0.16–0.27 (Spearman's ρ values), but strong in middle-aged persons, at 0.38–1.00. On receiver-operating characteristic (ROC) curve analysis for detection of insulin resistance, the ABSI had a lower area under the ROC curve (AUC) than the other anthropometric indices, and the BRI and the WC/Ht ratio showed similar AUCs. The AUCs for the BRI and WC/Ht ratio were the highest in middle-aged men with NGT and glucose intolerance. Conclusions: The BRI, not the ABSI, was better correlated with SI in young and middle-aged Japanese persons. The BRI and WC/Ht ratio were comparable in their correlations with SI and the detection of insulin resistance in the participants of the present study.


Introduction
D iabetes mellitus develops due to insufficient sensi- tivity and/or secretion of insulin. 1 In particular, type 2 diabetes mellitus, which accounts for *90% of all patients with diabetes mellitus, mainly develops due to insufficient sensitivity to insulin.As a risk factor for insufficient sensitivity to insulin, the importance of obesity has been established. 2Obesity is also reported to be associated with health problems such as cancer and cardiovascular disease. 3The body mass index (BMI), waist circumference (WC), and WC/Height (Ht) ratio have been used as indices of obesity for a long time. 4,5However, these traditional anthropometric indices cannot distinguish between mass containing fat (fat mass) and fat-free mass, making accurate classification of risk for obesity-related complications difficult. 6,7o improve the limitations of traditional anthropometric indices, a body shape index (ABSI) and body roundness index (BRI) have been developed. 8,91][12][13] These associations may be mediated by insulin resistance.5][16][17] In adults without diabetes, the ABSI is weakly correlated with SI, whereas the BRI shows a stronger correlation with SI, comparable to traditional anthropometric indices. 14,15In obese and young persons, it is the BRI, not the ABSI that is reportedly correlated with SI. 16,17 These epidemiological studies had small sample sizes and limitations in terms of age and glucose tolerance.To our knowledge, no study has examined the association between the ABSI and/or the BRI and indices of SI using the oral glucose tolerance test (OGTT) in a large and varied population.
The present study was performed to test the hypothesis that the ABSI and/or BRI is better related to SI than traditional anthropometric indices such as the BMI, WC, and WC/Ht.To test this hypothesis, the ABSI, BRI, and traditional anthropometric indices were compared with indices of SI using postload insulin levels based on a 75-g OGTT in a large sample divided mainly into three different groups: young persons with normal glucose tolerance (NGT), middle-aged persons with NGT, and middle-aged persons, including both those with NGT and those with glucose intolerance.

Participants
The study participants were 1270 medical students at Jichi Medical University, Tochigi, Japan (age <40 years) who had NGT, from among about 1400 students who had undergone a 75-g OGTT between December 2002 and April 2015.NGT was defined based on Japan Diabetes Society criteria [fasting plasma glucose (PG) <110 mg/dL and 120min value <140 mg/Dl]. 18The study was approved by the Ethics Committee at Jichi Medical University (approval no.EKI 09-45).Written, informed consent was obtained from all participants after providing full information on the purposes of the study ( Jichi cohort).Data collection was consistent throughout the study period in the Jichi cohort.
Data from health examinees, 30-65 years of age, at Hokuriku Central Hospital, Toyama, Japan, were also ana-lyzed.The detailed characteristics of the study population have been described elsewhere. 19,20Briefly, 2153 participants who visited the hospital between April 2006 and March 2010 were enrolled in this study after excluding those who had Hemoglobin A1c values ‡6.5%, who had a known history of diabetes mellitus and/or taking antidiabetic agents, who had undergone gastrectomy, who were taking steroids, or who were taking anticancer drugs.The study was approved by the Ethics Committee of the Hokuriku Central Hospital. 19,20Written, informed consent was obtained from all participants after providing full information on the purposes of the study (Hokuriku cohort).

Measurements and calculation of SI
PG concentrations were measured using a glucose oxidase assay, and insulin levels were measured using an immunoradiometric assay for immunoreactive insulin (IRI) (Insulin RIA Beads II; Yamasa, Tokyo, Japan), as described previously ( Jichi cohort). 21Serum IRI concentrations were determined using a chemiluminescence immunoassay (Siemens Healthcare Diagnostics, Tokyo, Japan) at a commercial laboratory (BML, Inc., Tokyo, Japan) (Hokuriku cohort). 19,20he antibodies used in both insulin assays did not cross-react with proinsulin.In the 75-g OGTT, PG and IRI levels were measured under fasting conditions (preloading) and 120 min after glucose loading; these are abbreviated as PG0 and PG120, and IRI0 and IRI120, respectively.
Similar to our previous studies, 21,22 the following measures were used.Systemic SI as determined by the Matsuda index (ISI-Matsuda) was calculated as: ISI-Matsuda = 10,000/[sqrt (PG0 • PG120 • IRI0 • IRI120)]. 23,24In addition, 1/homeostasis model assessment of insulin resistance (HOMA-IR) was used primarily as a measure of hepatic SI.HOMA-IR was calculated as [PG0 • IRI0/405]. 25The units for PG and IRI were milligrams per deciliter and microunits per milliliter for calculating ISI-Matsuda and HOMA-IR.Negative values were treated as missing.
The 25th percentile for ISI-Matsuda and 1/HOMA-IR in the NGT of each cohort was adopted as the cutoff for decreased SI, that is, insulin resistance.The 25th percentile was adopted according to the previous study. 16In the Jichi cohort, an ISI-Matsuda of £6.1 and a 1/HOMA-IR of £0.562 were used.In the Hokuriku cohort, an ISI-Matsuda of £7.7 and a 1/HOMA-IR of £0.827 were used.

Questionnaires and measurements of background factors
Data on age and sex were obtained through questionnaires.High-density lipoprotein cholesterol (HDL), triglyceride (TG), and total cholesterol (T-chol) levels were measured using serum collected under fasting conditions.The units for HDL, TG and T-Chol were milligrams per deciliter.The low-density lipoprotein cholesterol (LDL) concentration was calculated using the Friedewald formula (LDL = T-chol -HDL -TG/5). 26Blood pressure (BP) (systolic BP and diastolic BP) were measured after the participant had been seated at rest for 5 min.

Measurements of anthropometric indices
BMI was calculated as the weight in kilograms divided by the height (Ht) in meters squared.WC was measured at the umbilical level with the subject standing. 27The WC/Ht ratio was also calculated.ABSI, which has been reported, 8 was calculated as: WC/BMI 2/3 /Ht 1/2 .The BRI, which has also been reported, 9 was calculated as: 364.2-365.5

Statistical analyses
JMP version 5.1 was used for all statistical analyses, except for the receiver-operating characteristic (ROC) curve analysis.Since almost none of the variables had a normal distribution, results are expressed as median (25th percentile, 75th percentile) values.The correlations of anthropometric indices with SI were tested using Spearman's rankcorrelation coefficients on bivariate analysis.
ROC curves and the area under the ROC curves (AUCs) were used to assess the ability of each anthropometric index to detect insulin resistance, using EZR ver.1.61 (Saitama Medical Center, Jichi Medical University, Saitama, Japan). 28If the lower limit of the 95% confidence interval for the AUC of an anthropometric index was below 0.50, that index was considered to not have the ability to detect insulin resistance.Differences in two AUCs were assessed by the method described by Delong. 29Optimal cutoff values of anthropometric indices were determined by maximization of the Youden index (sensitivity+specificity -1).For all statistical tests, values of P < 0.05 were considered significant.

Characteristics of the entire cohort
The characteristics of the study participants by sex are shown in Table 1.The Jichi cohort (n = 1270) included only persons with NGT and was a young cohort with few cases of obesity, hypertension, and dyslipidemia.The participants in the Hokuriku cohort were sorted into an NGT-only group (n = 1531) and a group that included those with NGT and those with glucose intolerance (n = 2153).Both groups in the Hokuriku cohort consisted of middle-aged persons who had higher BMI, WC, WC/Ht ratio, BP, lipids, and glucose than the young persons with NGT (the Jichi cohort).The Hokuriku cohort included 622 persons with glucose intolerance (nondiabetic hyperglycemia, n = 547; newly diagnosed diabetes mellitus, n = 75), accounting for 29% of the total cohort.The group in the Hokuriku cohort that included those with NGT and those with glucose intolerance did not appear to have any major differences in age, BMI, WC, height, WC/Ht ratio, BP, or lipids compared with the NGT group of the same cohort; however, their glucose levels were higher 120 min after glucose loading, and their ISI-Matsuda was low.
The ABSI did not differ between any of the cohorts or between the sexes, ranging from about 0.7 to 0.8.
The BRI was higher in the Hokuriku cohort than in the Jichi cohort.Men had a higher BRI and BMI than women in the Jichi cohort.The BMI was lower in women in the Hokuriku cohort, but the women had a higher BRI than the men.

Relationships of anthropometric indices with SI in each cohort
In both men and women in the Jichi cohort (young persons with NGT), BRI showed similar or high inverse correlations with 1/HOMA-IR and ISI-Matsuda compared with the BMI, WC, and WC/Ht ratio, whereas the ABSI showed a weak inverse correlation (Table 2).In both men and women among the middle-aged persons with NGT and glucose intolerance, those with NGT, and those with glucose intolerance in the Hokuriku cohort, the BRI showed almost the same inverse correlation with 1/HOMA-IR and ISI-Matsuda compared with the BMI, WC, and WC/Ht ratio, whereas the ABSI showed a weak inverse correlation (Table 2).Spearman's r values for SI of the BRI were higher in men in the Jichi cohort, and similarly, those for SI of the BRI were higher in men with NGT and glucose intolerance, and in men with glucose intolerance in the Hokuriku cohort.Overall, Spearman's r values for each anthropometric index and SI for both men and women were higher in the Hokuriku cohort than in the Jichi cohort (Table 2).
The distribution of each of the anthropometric indices for ISI-Matsuda in participants with NGT in both cohorts is shown in Fig. 1.The range of ISI-Matsuda and each of the anthropometric indices increased more in middle-aged persons with NGT in the Hokuriku cohort than in the Jichi cohort (young persons with NGT).ISI-Matsuda showed a particularly wide distribution (Table 1 and Fig. 1).

ROC analyses
The results of the ROC analyses using each of the anthropometric indices for the presence or absence of insulin resistance based on ISI-Matsuda are shown in Table 3.The active model of the ROC curve could not be generated by EZR for women in the Jichi cohort.The AUCs were significant for the ability of the BMI, WC, WC/Ht ratio, ABSI, and BRI in men of the three cohorts and women of the Hokuriku cohort to identify insulin resistance.The AUCs were not significant for the ability of the ABSI to identify insulin resistance in women of the Jichi cohort.In addition, the ABSI showed the lowest AUCs in all men and women of these cohorts.
In both men and women of these cohorts, the BRI and WC/Ht ratio generally scored the highest and showed almost the same AUCs.In women in the Hokuriku cohort, the BMI showed a similar AUC to the BRI and WC/Ht ratio.The AUCs for the BRI and WC/Ht ratio were the highest in middle-aged men, including those with NGT and glucose intolerance, and those with glucose intolerance (Hokuriku cohort).
The results of ROC analyses using each of the anthropometric indices for the presence or absence of insulin resistance based on 1/HOMA-IR were mostly similar to those based on ISI-Matsuda (Supplementary Table S1).

Discussion
The present study investigated whether the BRI and ABSI correlate better with SI than traditional anthropometric indices such as the BMI, WC, and WC/Ht ratio.The BRI showed comparable correlations to the BMI, WC, and WC/Ht ratio in both men and women among young persons, middle-aged persons with NGT, and middle-aged persons, including those with NGT and those with glucose intolerance.However, in the participants of the present study, the BRI did not correlate better with SI than traditional anthropometric indices, especially the WC/Ht ratio.On the other hand, the correlation between the ABSI and SI was weaker than for the other anthropometric indices in all groups.The correlation coefficient between each anthropometric index and SI was higher in  middle-aged persons than in young persons.On ROC curve analysis for detection of insulin resistance, the ABSI showed a smaller AUC than the other anthropometric indices, and the BRI and WC/Ht ratio showed similar AUCs in both men and women.The largest AUC was seen in middle-aged men, including those with glucose intolerance.3][14][15][16][17] The results of the present study are consistent with results to date.In epidemiological studies, carrying out an OGTT is difficult, and postload insulin levels in particular are often impossible to measure.Many studies therefore cannot measure SI such as by ISI-Matsuda.In the present study, ISI-Matsuda was used as an index of SI, and the correlation with each of the anthropometric indices could be calculated in a population of varied age and glucose tolerance.
The BRI was higher in the middle-aged Hokuriku cohort than in the young Jichi cohort in both men and women.
The BRI was higher in young men than in young women, and higher in middle-aged women than middle-aged men.This is thought to be because, in the Jichi cohort, the WC of women was much smaller than that of men, but the sex difference in Ht was small, whereas in the Hokuriku cohort, women were shorter in Ht, but had a larger WC.Compared with the ABSI, the BRI showed a better correlation with SI in both cohorts.The BRI is more reflective of central obesity and is thought to show a good correlation with SI. 9,30 On the other hand, the ABSI values were similar in all groups of both cohorts and correlated poorly with SI.The methods of calculating the BRI and ABSI differ, in that the WC is divided by BMI 2/3 in the latter, suggesting a possible weakening of the correlation of WC to SI.In the present study, the ABSI correlated poorly with the other anthropometric indices in men and women of all cohorts, and, in particular, the correlation between the ABSI and BMI was not significant (Spearman's rank correlation, data not shown).This also suggests that the ABSI has different properties from other body anthropometric indices.SI and each of the anthropometric indices showed a better correlation in the middle-aged Hokuriku cohort than in the young Jichi cohort.In both men and women of the middleaged Hokuriku cohort, BMI and WC increased, with a high possibility of many participants with low physical activity.On the other hand, in the Jichi cohort, the physical activity of individuals could not be analyzed, but *80% of the participants exercised regularly.The differences in physical activity likely affected the correlation between SI and each anthropometric index.Furthermore, in the middle-aged Hokuriku cohort, the increased ranges of SI and each anthropometric index may have been another factor for the good correlation.
On ROC examination for the presence or absence of insulin resistance based on ISI-Matsuda, the AUC for the ABSI was small in all cohorts.This is consistent with the poor correlation between SI and the ABSI.The BRI is calculated using WC and Ht, which affected the finding that the AUCs of the BRI and WC/Ht ratio were similar.In fact, the correlations between the anthropometric indices in the present study were very strong for the BRI and WC/Ht ratio in men and women in all cohorts (Spearman's r values were nearly 1).In an earlier report, the AUCs of the BRI and WC/Ht ratio for insulin resistance were similar, 15 as in the present study.The AUC was generally larger in the middleaged Hokuriku cohort compared with the young Jichi cohort.In the middle-aged Hokuriku cohort, the BRI and WC/Ht ratio in men and the BMI, BRI, and WC/Ht ratio in women showed high sensitivity and specificity and a large AUC, whereas the BRI and WC/Ht ratio showed the highest sensitivity and specificity and the largest AUC, particularly in men, including those with glucose intolerance.
The results of these ROC analyses were consistent with the correlations of anthropometric indices to the SI.The ability of the BRI to detect insulin resistance was comparable to that of traditional anthropometric markers such as the WC/Ht ratio.
Numerous reports have examined the correlations between SI and anthropometric indices such as the BMI, [14][15][16][17][31][32][33][34] and many studies included a large number of obese persons. In thepresent study, a linear correlation was seen between anthropometric indices and SI in two cohorts containing mostly nonobese persons (Fig. 1).East Asians are known to have a lower BMI, but have a higher likelihood of developing diabetes mellitus than Westerners.35,36 In young and middle-aged East Asians, maintaining an appropriate body weight may help maintain SI and inhibit the development of glucose intolerance.
Unexpectedly, indices of SI tended to be better in the middle-aged Hokuriku cohort than in the young Jichi cohort, despite increases in the BMI and WC.One simple explanation for this is the difference in the method of measuring insulin.However, some young persons are known to excrete too much insulin to glucose load; such hypersecretion of insulin may be a precursor to glucose intolerance. 37,38Many reports have noted that insulin secretion decreases with aging, 39,40 and differences in insulin levels may be due to differences in age.The above points meant that comparison of insulin levels and indices of SI between the two cohorts was difficult, and a combined analysis of both groups could not be performed.However, the aim of the present study was not to compare the indices of SI of the two cohorts.The investigation of the correlation between anthropometric indices and SI was performed in each cohort, and cutoff values were set in each cohort in the ROC analysis for detection of insulin resistance.Therefore, differences in insulin-measuring methods did not appear to affect the results.
Further limitations of the present study were that no elderly persons or a large number of diabetic patients could be examined, few obese persons were included, and hip circumference (Hc) could not be measured.Unfortunately, the relative merits of the WC/Ht ratio and the WC/Hc ratio could not be investigated.In addition, the participants of the present study were limited to Japanese people.The anthropometric indices and SI of Japanese people and Westerners differ greatly, and HOMA-IR is reported to differ even with an equivalent BMI. 41It is unclear whether the results also apply to other populations, such as Westerners.The use of insulin sensitizers as antidiabetic agents may decrease insulin levels, and thereby, affect SI indices.However, participants taking antidiabetic agents were excluded in the Hokuriku cohort, and not included in the Jichi cohort.The use of antihypertensive agents may also increase and/or decrease SI.In the overall Hokuriku cohort, 222 men and 83 women had taken antihypertensive agents.
Spearman's rank coefficients of anthropometric indices for 1/HOMA-IR and ISI-Matsuda, excluding those taking antihypertensive agents were exactly identical to those of the overall Hokuriku cohort (data not shown).Effects of the use of antihypertensive agents seem to be minor.

Conclusions
In conclusion, in young and middle-aged Japanese people, the BRI, and not the ABSI, was better correlated with the SI, and the BRI was comparable to the WC/Ht ratio in detecting insulin resistance.In addition to traditional anthropometric indices, such as the BMI, the BRI may be clinically useful as a marker for predicting the onset of metabolic syndrome and diabetes mellitus.A follow-up study of the development of glucose intolerance in the Jichi and Hokuriku cohorts is in progress.

BODY ROUNDNESS INDEX AND INSULIN SENSITIVITY Table 1 .
Characteristics of the Participants in the Jichi and Hokuriku Cohorts Jichi cohort (young NGT) Hokuriku cohort (middle-aged NGT) Hokuriku cohort, including NGT and glucose intolerance (middle-aged overall)

Table 3 .
Area Under the Curve, Sensitivity and Specificity of Cutoff Values of Anthropometric Indices for the Presence of Insulin Resistance by ISI-Matsuda in Both SexesFor the presence of insulin resistance by ISI-Matsuda P < 0.001/Versus WC/Ht ratio, ABSI and BRI, P < 0.0001.